Drug Design, Development and Therapy
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Management of difficult-to-treat patients
with ulcerative colitis: focus on adalimumab
Alessandro Armuzzi
Daniela Pugliese
Olga Maria Nardone
Luisa Guidi
IBD Unit, Complesso Integrato
Columbus, Catholic University,
Rome, Italy
Correspondence: Alessandro Armuzzi
Complesso Integrato Columbus,
Catholic University, Via G. Moscati
31-33 00168 Rome, Italy
Tel+39 06 350 3310
Fax +39 06 305 4641
Email alearmuzzi@yahoo.com
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http://dx.doi.org/10.2147/DDDT.S33197
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This article was published in the following Dove Press journal:
Drug Design, Development and Therapy
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Abstract: The treatment of ulcerative colitis has changed over the last decade, with the intro-
duction of biological drugs. This article reviews the currently available therapies for ulcerative
colitis and the specific use of these therapies in the management of patients in different settings,
particularly the difficult-to-treat patients. The focus of this review is on adalimumab, which
has recently obtained approval by the European Medicines Agency and the US Food and Drug
Administration, for use in treating adult patients with moderate-to-severe, active ulcerative
colitis, who are refractory, intolerant, or who have contraindications to conventional therapy,
including corticosteroids and thiopurines. Since the results emerging from the pivotal trials
have been subject to some debate, the aim of this review was to summarize all available data
on the use of adalimumab in ulcerative colitis, focusing also on a retrospective series of real-life
experiences. Taken together, the current evidence indicates that adalimumab is effective for
the treatment of patients with different types of ulcerative colitis, including biologically nave
and difficult-to-treat patients.
Keywords: randomized controlled trials, real-life experiences
Introduction
Ulcerative colitis is a chronic inflammatory disease of the large intestine. Its exact cause
is unknown, but it appears to be multifactorial, with a proposed interaction between
genetic and environmental factors that results in continuous activation of the intestinal
mucosal immune system. The inflammation affects the mucosa of the rectum, with
different degrees of involvement of the colon.1 The management of ulcerative colitis
is based on the extent of colon involvement, the activity, and the behavior of disease.
The classification of the disease is defined according to the Montreal Classification,
which describes the maximal macroscopic extent of the disease at colonscopy.2 This
has important prognostic and management implications because patients with extensive
ulcerative colitis bear a higher risk of colectomy and cancer,3 and patients with proctitis
and left-sided colitis obtain much more benefit from topical therapies. However, the
extent of colon involvement may change over time, such that about 20% of patients
who are diagnosed with proctitis or left-sided ulcerative colitis are found to have
proximal extension of the inflammation at follow-up.
The clinical course of ulcerative colitis is characterized by different disease onsets
and a remittingrelapsing course. A recent population-based, inception cohort study
identified four different patterns: (1) initial high activity that decreases to remission or
mild severity (55% of patients); (2) initial low activity that changes to increased
severity (1% of patients); (3) continuous symptoms (6% of patients); and (4) chronic
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which permits unrestricted noncommercial use, provided the original work is properly cited.
Armuzzi etal
intermittent symptoms (37% of patients). Moreover, an initial
presentation with extensive colitis, high systemic inflam-
mation burden, and a younger age has been associated with
higher subsequent colectomy rates.4 Disease activity is com-
monly classified as: remission, mild, moderate, or severe.
Over the years, several different scoring systems have been
developed as measures of disease activity, but most of these
have only been used in clinical trials and have not been
validated. In clinical practice, the combination of clinical
features, laboratory findings, and the endoscopic appearance,
forms the basis of patient management.5
Management of ulcerative colitis
The main treatment goals for ulcerative colitis are the induc-
tion and maintenance of clinical and endoscopic remission.
As far as mild-to-moderate disease is concerned, the oral and
topical aminosalicylates represent the standard therapy for
achieving this outcome.6 In the event of inadequate response
to aminosalicylates and in patients with moderate-to-severe
disease, systemic corticosteroids are the best option for induc-
ing remission.7 Patients with active ulcerative colitis who do
not have significant clinical improvement after 24 weeks
of an appropriate course of corticosteroids are classified as
corticosteroid-refractory. Anti-tumor necrosis factor-alpha
(TNF) monoclonal antibodies represent the best available
option for this group of patients, achieving clinical and endo-
scopic remission without prolonged steroid exposure.8
After achieving a response with corticosteroid treatment,
aminosalicylates are usually continued as maintenance therapy.
However, patients relapsing within 3months of stopping cor-
ticosteroids or who are not able to reduce the dose to below
10mg/day of prednisolone within 3months of starting are
classified as corticosteroid dependent.1 In this specific dis-
ease setting, azathioprine has been shown to be significantly
more effective than mesalazine for inducing corticosteroid-
free clinical and endoscopic remission at 6months and has
a corticosteroid-sparing effect.9 Treatment algorithms for
patients with corticosteroid-dependent ulcerative colitis
suggest starting concomitant thiopurine therapy and slowly
withdrawing corticosteroids over 34months, timed to coin-
cide with the expected onset of action of the thiopurines.10 If
symptoms persist or patients are unable to stop steroids after
12 weeks of starting thiopurines, anti-TNF agents should be
started.10 Finally, induction and scheduled maintenance treat-
ment with infliximab has been recently reported to be effec-
tive for inducing steroid-free clinical remission and mucosal
healing at 1 year, in both thiopurine-nave and experienced,
corticosteroid-dependent, ulcerative colitis patients.11
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Patients with acute, severe ulcerative colitis need to be
hospitalized and treated with intensive intravenous corti-
costeroids (methylprednisolone, 60mg/24 h, or hydrocor-
tisone, 100 mg, four times daily). A lack of improvement
within 35days of intensive treatment is an indication for
rescue therapy or surgery. A recent open-label trial involving
115 patients with acute, severe ulcerative colitis who were
refractory to intravenous corticosteroids and randomized to
receive either intravenous cyclosporine or infliximab has
shown no significant differences in treatment failure (primary
efficacy outcome: 60% cyclosporine group vs 54% infliximab
group; absolute risk difference, 6%; 95% confidence interval
[CI], 7 to 19 [P=0.52]).12
Therefore, the decisions of physicians are often deter-
mined on a case-by-case basis. These decisions are usually
made based on personal experiences with this specific
therapy and the physicians confidence for the management
of adverse events, taking into account the long-term strategy.
Cyclosporine, in fact, has been shown to be effective only
over the short-to-medium term. Therefore, all patients should
be bridged to thiopurines, although it has been shown that
patients without previous thiopurine exposure have better
outcomes.13
Adalimumab in ulcerative colitis
Adalimumab is a human monoclonal immunoglobulin (Ig)
G1 antibody to TNF that is subcutaneously administered
at a standard induction dose of 160mg, followed by 80mg
after 2 weeks. Maintenance doses are then scheduled at 40mg
every other week (EOW).14 This drug has been shown to be
effective for inducing and maintaining remission in patients
with active, moderate-to-severe luminal or perianal Crohns
disease; patients nave to anti-TNF; or patients with previ-
ous loss of response or intolerance to infliximab.1519
As far as ulcerative colitis is concerned, after the publica-
tion of the results of the two pivotal, randomized, placebo-
controlled, double-blind trials (ULTRA 1 and 2) (Table1),20,21
adalimumab was approved for use in patients with moderate-
to-severe active disease and in those who were nonresponders
or intolerant to conventional therapy. In these trials, involv-
ing more than 1000 patients with moderate-to-severe active
ulcerative colitis, adalimumab was compared with placebo
with regard to the efficacy of induction and as a maintenance
treatment, assessed after 8 and 52 weeks, respectively.
In the ULTRA 1 trial,20 patients with ulcerative colitis
were initially randomized to adalimumab (160mg/80mg) or
placebo at weeks 0 and 2, respectively. Subsequently, after
an amendment of the protocol, a third arm, with adalimumab
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Table 1 Outcome parameters from studies on adalimumab in ulcerative colitis

Study Study Number Induction of clinical Maintenance of clinical Steroid Mucosal Colectomy
(references) type of patients response/remission response/remission sparing healing (%)
(%) (%) (%) (%)
ULTRA 120 RCT 390 Week 8: 54.6%/18.5% Week 8:
46.9%
ULTRA 221 RCT 494 Week 8: 50.4%/16.5% Week 52: 34.6%/17.3% 37.8% Week 8:
41.1%
Week 52:
25%
Oussalah OL 13 42 weeks mean FU: 46.2%
et al27 38.5% clinical benefit
Afif et al28 OL 20 Week 8: 25%/5% Week 24: 50%/25% 58%
Hudis et al29 RS 9 56%
Gies et al30 OL 25 Week 14: 80%/ 54.5 weeks median FU: 100% 8%
70%/
Taxonera RS 30 Week 12: 60%/26.7% 48 weeks median FU: 68% 20%
et al31 50%/
Ferrante RS 50 Week 4: 68%/ 23 months median FU: 20%
et al33 52%/
McDermott RS 23 23 months median FU:
et al32 35% clinical benefit
Garca-Bosch RS 48 Week 12: 70.8%/50% Week 54: 35%/30% 22.9%
et al34
Armuzzi RS 88 Week 12: /28.4% Week 54: /43.2% 56.7% 26.3% 25%
et al35
Abbreviations: RCT, randomized controlled trial; OL, open-label study; RS, retrospective study; FU, follow-up.

at 80mg/40mg, was included. All patients enrolled were
nave to anti-TNF therapy and had active disease (defined
by a full Mayo score of 612 and an endoscopic subscore
of 23), despite stable doses of concomitant steroids, immu-
nomodulators, or both. The primary endpoint, assessed in
390 patients with ulcerative colitis who were studied after
the above amendment, was defined as the proportion of
patients achieving clinical remission (full Mayo score # 2,
with no individual subscore.1) by week 8in each treat-
ment arm. Week 8 clinical remission was achieved in 18.5%
of patients in the adalimumab 160/80 mg group and in
9.2% of patients in the placebo arm (P=0.031), showing
a 9.3% of therapeutic gain. The week 8 clinical remission
rate in the adalimumab 80/40mg group was similar to that
of the placebo group (10% vs 9.2%) (P=0.833). The clini-
cal response and mucosal healing among the three groups
(secondary endpoints) were not significantly different. A post
hoc analysis identified baseline clinical variables, such as
extensive disease, high disease activity (Mayo score $10)
and high levels of systemic inflammation (C-reactive
protein=10mg/L), that were associated with a low propor-
tion of patients in clinical remission, which might reflect a
lesser efficacy of adalimumab in patients with more severe
disease. Thereafter, 390 patients entered an open-label exten-
sion study after week 8 and were maintained on adalimumab
40 mg EOW for 52 weeks, with the possibility of dose-
escalation to 40mg weekly. A clinical remission at week 52
was reported in 25.6% of patients maintained with 40mg of
adalimumab EOW. A post hoc analysis, which included the
patients who dose-escalated to 40mg weekly, showed that
29.5% of patients were in remission at week 52.22
In the ULTRA 2 trial, 494 active ulcerative colitis
patients were randomized to receive adalimumab 160 mg
at week 0, 80mg at week 2, and 40mg EOW, or placebo,
through to 52 weeks. The clinical and endoscopic eligibil-
ity characteristics were similar to those associated with
the ULTRA 1 study, with the exception of the inclusion of
ulcerative colitis patients (40% of the population studied)
who had already experienced anti-TNF agents, but with
a discontinuation period of at least 8 weeks. The two co-
primary endpoints were defined as the proportion of patients
achieving clinical remission (defined as full Mayo score # 2,
with no individual subscore.1) at week 8 and the proportion
of patients achieving clinical remission at week 52. Clinical
remission at week 8 was achieved in 16.5% of patients in
the adalimumab arm and in 9.3% of patients in the placebo
arm (P=0.019) (7.2% therapeutic gain). The correspond-
ing values at week 52 were 17.3% and 8.5% (P=0.004),
respectively, with an absolute difference of adalimumab
versus placebo of 8.8%. Moreover, a clinical response was

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Armuzzi etal
achieved in 50.4% of patients receiving adalimumab and
34.6% on placebo (P,0.001) at week 8 and in 30.2% and
18.3%, respectively (P = 0.002) at week 52. The benefit
over placebo was also significant by endoscopic remission,
evaluated at week 8 (41.1%, adalimumab vs 31.7%, placebo)
(P=0.032) and at week 52 (25% vs 15.4%, respectively)
(P=0.009). A subgroup analysis, stratifying patients based
on prior exposure to anti-TNF, was also performed. Among
nave patients, a week 8 clinical remission was achieved in
21.3% of patients in the adalimumab group and in 11% in
the placebo group (P=0.017); the corresponding values at
week 52 were 22% and 12.4%, respectively (P = 0.029).
A significant difference in clinical remission was found
only at week 52 (10.2%, adalimumab and 3%, placebo)
(P=0.039) in the anti-TNF-exposed group.21
A post hoc intention-to-treat analysis of ULTRA 2,
including all patients randomized to adalimumab who
achieved a clinical response, as per their partial Mayo score
at week 8, was performed to investigate week 52 clinical
remission, response, mucosal healing, corticosteroid-free
remission, and corticosteroid discontinuation rates. Among
the 248 patients originally randomized to adalimumab,
123 (49.6%) had achieved clinical response. Of these, 30.9%,
49.6%, and 43.1% achieved clinical remission, clinical
response, and mucosal healing at week 52, respectively. Of
the 150 adalimumab-treated patients taking corticosteroids
at enrollment, 90 (60%) responded, as per their partial Mayo
score at week 8. Of these, 21.1% achieved corticosteroid-free
remission and 37.8% were corticosteroid-free at week 52,
without significant differences among the anti-TNF-nave
and exposed patients. These results were similar whether or
not week 8 responses were assessed using the full Mayo
score.23 Further analysis showed that patients who received
the 160mg/80mg adalimumab induction dose had a signifi-
cantly lower risk of all-cause hospitalizations and ulcerative
colitis-related hospitalizations, compared with placebo, dur-
ing the first 8 weeks of therapy.24 This benefit over placebo
was also significant for adalimumab early-responders, during
the follow-up.25
At 52 weeks, 588 patients who completed the ULTRA
12 trials entered an extension, open-label study. Patients who
entered the open-label, weekly adalimumab study continued at
the same dose. Patients who entered the study from any blinded
arm or from an open-label cohort receiving adalimumab
(40mg EOW) received adalimumab at a dose of 40mg EOW.
At week 60 of the open-label extension study, 351 (59.7%)
of the patients who had entered the extension study achieved
clinical remission, per their partial Mayo score.26
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Adalimumab in ulcerative colitis:
real-life data
Although adalimumab has been recently licensed, multiple
lines of evidence from open-label and retrospective studies
on adalimumab, administered for compassionate use in ulcer-
ative colitis patients, have been available for several years
(Table1). Oussalah etal27 first presented data on 13 ulcerative
colitis patients treated with adalimumab in 2008. All of the
patients had been previously treated with infliximab, and
most of them (90.31%) had been previously treated with
thiopurines. Patients were treated with adalimumab, with
an induction dose of 160/80mg at weeks 0 and 2, and then
maintained with 40 mg EOW. The primary endpoint was
defined as the proportion of patients on adalimumab therapy
during the study. After a median follow-up of 41 weeks, the
percentage of patients remaining on adalimumab therapy
was 32.5%. Eight patients discontinued adalimumab: six
due to colectomy, one due to lack of response, and one due
to an exacerbation of psoriasis. No significant differences
were found in adalimumab withdrawal and colectomy rates
between the patients who lost response to infliximab and
those who became intolerant. From this small cohort of
difficult-to-treat patients who had already been treated with
all of the main available therapies, adalimumab treatment
potentially avoided colectomy in about half of them.
One year later, the Mayo Clinic Group published the
results of an uncontrolled, open-label study on adalimumab in
20 patients with ulcerative colitis, of whom 35% were nave
to infliximab. All patients had active disease (defined as a
Mayo score of 612 points, with an endoscopic subscore of
at least 2) despite concurrent treatment (steroids, and/or thio-
purines, and/or aminosalicylates). Patients were treated with
adalimumab at an induction dose of 160/80mg at weeks 0
and 2, respectively, and maintained with 40mg EOW. The
primary endpoint was defined as the proportion of patients
achieving a clinical response at week 8. The percentages
of patients who had a clinical remission or response were
5% and 25% at week 8, respectively and 25% and 50% at
week 24, respectively. No significant differences were found
between infliximab-nave and infliximab-exposed patients.
Among the patients who entered the trial on corticosteroids,
58% were able to withdraw by week 24, showing the potential
effectiveness of adalimumab as a steroid-sparing agent.28
Hudis et al 29 retrospectively reported data on nine
patients, with active ulcerative colitis (mean Mayo score of
61.66 at baseline) and secondary infliximab failure, who
were treated with adalimumab (induction, 160/80 mg at
weeks 0/2; maintenance, 40mg EOW). During the follow-up,
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adalimumab was found to be effective at inducing a clinical
response (mean Mayo score, 2.51) (P,0.0005), with a
steroid-sparing effect (P,0.003).
Gies etal,30 in 2010, also reported real life data, from
a single referral center, involving 53 ulcerative colitis out-
patients treated with biologic drugs, following a structured
protocol for a step-up approach. All patients were intoler-
ant and/or nonresponders to conventional therapy, including
aminosalicylates, steroids, and thiopurines. Among them,
25 patients were treated with adalimumab (160/80 mg at
weeks 0 and 2, then 40mg EOW) and 28 with infliximab
(5mg/kg at weeks 0, 2, and 6, then every 8 weeks). Most
of patients had extensive colitis (96% in the adalimumab
group and 90% in the infliximab group). Concomitant
immunosuppressive therapy (azathioprine or methotrexate)
was taken by significantly fewer patients in the adalimumab
group (20% vs 53.4%) (P=0.0118). The primary endpoint
was defined as the proportion of patients treated with adali-
mumab or infliximab achieving and maintaining a clinical
response. At 14 weeks, 47 of the 53 (88.7%) patients had a
clinical response to anti-TNF therapy, without a significant
difference between the adalimumab (20/25 patients, 80%)
and infliximab (27/28 patients, 96%) groups (P=0.0889).
Among the patients who entered the maintenance treatment
phase, 1420 adalimumab (70.0%) and 1418 (77.8%) inf-
liximab patients had a response up to the end of follow-up
(P=0.7190). The median duration for the maintenance phase
was 54.5 weeks (range, 3108 weeks) for the adalimumab
group and 64.5 weeks (range, 8180 weeks) for the infliximab
group. Of the six adalimumab patients who lost response,
two underwent colectomy, one switched to infliximab, and
three were treated with another course of steroids. About
92% of the patients who were initially taking steroids were
able to stop over the course of the maintenance period, with
similar results observed in both groups. Thus, in this real
life cohort, adalimumab seemed to be as effective as inf-
liximab at achieving induction and maintenance responses
in ulcerative colitis patients.
The effectiveness of adalimumab in a real-life setting has
also been reported in a Spanish retrospective multicenter study
that enrolled 30 ulcerative colitis patients after the failure of
other therapies. All patients were infliximab experienced:
53.3% had lost responsiveness, 40% had become intolerant,
and 6.7% were primary nonresponders. Adalimumab was
administered to 26 patients because of moderate-to-severe,
refractory ulcerative colitis, and four patients received
adalimumab because of a severe attack that was refrac-
tory to intravenous corticosteroids. All patients received a
Drug Design, Development and Therapy 2013:7
Adalimumab in the management of ulcerative colitis
loading dose of 160/80mg of adalimumab at weeks 0 and 2,
respectively and were maintained with 40mg EOW. Patients
were assessed at weeks 4 and 12, and then every 4 weeks
in order to evaluate the short- and long-term outcomes. The
primary endpoint was defined as the induction of a clinical
response at week 12. Sixteen (53.3%) and 18 (60%) patients
achieved a clinical response at week 4 and 12, respectively.
Three (10%) and eight (26.7%) patients achieved a clinical
remission at week 4 and 12, respectively. Fifteen (50%)
patients discontinued adalimumab during the median
follow-up of 48 weeks (interquartile range [IQR], 16104),
and 13 (86.6%) of them discontinued because of a lack or loss
of response, including four inpatients with severe intravenous
corticosteroid-refractory disease. All patients who were
under corticosteroid treatment at baseline and entered the
maintenance adalimumab treatment were able to discontinue
the steroids. The rate of colectomy was 20%, with a median
time to colectomy of 16 weeks (IQR, 5.240.5 weeks).
A lack of response at week 12 was associated with an
increased probability of withdrawal (P=0.001) and a higher
rate of colectomy (P=0.001). Thus, adalimumab induced
a durable clinical response in a good percentage of patients
with medically refractory ulcerative colitis, especially in
those who achieved short-term clinical response.31
The same issue was also addressed by McDermott etal,32
who collected data on 23 patients with ulcerative colitis
treated with adalimumab (standard induction and mainte-
nance treatment). Twenty-two of the patients (96%) had
received prior immunomodulatory therapy and 20 (86%) had
previously been treated with infliximab (three primary nonre-
sponders, eleven secondary failures, and six who experienced
side effects). The primary endpoint was defined as treatment
failure. During a median follow-up period of 22months (IQR,
832months), 16 patients (69.5%) discontinued adalimumab.
The reasons for discontinuation were primary nonresponse
in six patients (37%), secondary nonresponse in eight (50%),
and side effects in one (6%). Nine patients underwent colec-
tomy, and three refused surgery; the colectomy-free survival
was estimated to be 78% at 6months, 70% at 12months,
and 59% at 2 years. No significant predictors of colectomy
were identified, but 55% of patients who underwent surgery
had failed adalimumab treatment within 3months of starting
treatment.32
Further findings by Ferrante etal33 confirmed that adali-
mumab is effective in inducing a durable clinical remission in
patients who have already been treated with infliximab. Fifty
patients with moderate-to-severe ulcerative colitis received
adalimumab induction treatment (160/80 mg at weeks 0
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Armuzzi etal
and 2, followed by 40 mg EOW). The primary endpoint
was the long-term efficacy of adalimumab. At week 4, 68%
patients showed a short-term clinical response. In particular,
22% of the patients achieved a complete clinical response,
defined as the absence of diarrhea and bloody stools, and
46% of the patients achieved a partial response, defined as
a marked clinical improvement, with persisting rectal blood
loss. After a median follow-up of 23months, 52% achieved a
durable response to adalimumab, defined as a lasting clinical
response. Colectomy was necessary in 20% of patients. Dose
escalation was necessary in 76% of patients and was associ-
ated with significantly increased serum adalimumab levels
(from 4.75 to 7.95g/mL) (P=0.023). Short-term clinical
response and response to dose escalation were associated
with colectomy-free survival (P = 0.030 and P , 0.001,
respectively).
Data from the Spanish ENEIDA (Estudio Nacional en
Enfermedad Inflamatoria Intestinal sobre Determinantes
genticos y Ambientales) registry of 48 patients with
ulcerative colitis treated with adalimumab (induction
dose, 160/80mg at weeks 0 and 2, in 93.7% of patients;
maintenance dose, 40 mg EOW) have been recently
reported.31 Among these patients, 39 (81.3%) had previ-
ously received infliximab and were categorized into one of
three categories: remission, 51.3%; response, 33.3%; and
primary nonresponse, 15.4%. The primary endpoint was
defined as the proportion of patients achieving a clinical
response during the follow-up period. The clinical response
rates were assessed at weeks 12, 28, and 54 and were 70.8%
(34/48), 43.2% (19/44), and 35% (14/40), respectively.
A response to prior treatment with infliximab was the only
factor predictive of a response to adalimumab at week 12,
which was obtained in 90% of infliximab remitters, 53.8% of
responders, and 33.3% of primary nonresponders (P=0.01).
Eleven patients (22.9%) needed colectomy after a mean time
of 205days. A lack of response to adalimumab at week 12
was shown to be an independent predictor of colectomy:
five of the 34 (14.7%) responders and six of the 14 (42.9%)
nonresponders (P = 0.035) required a colectomy, with a
colectomy-free time that was significantly reduced among
the nonresponding patients (P=0.01).34
The last real-life experience comes from an Italian mul-
ticenter study that represents the largest case series of active
ulcerative colitis treated with adalimumab. Eighty-eight
patients were treated with adalimumab (induction dose of
160mg/80mg in 77 patients [87.5%] and 80mg/40mg in
eleven patients [12.5%], at weeks 0 and 2, respectively). After
induction, the patients were maintained with adalimumab
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40mg EOW; a dose escalation was allowed at the physicians
discretion. All patients had active disease (medium partial
Mayo score, 6) (IQR, 48), and 57 (64.8%) had extensive
colitis. Sixty-nine patients (78.4%) had been previously
treated with infliximab, and 65 (73.9%) had been exposed
to immunomodulators (azathioprine, methotrexate, and
cyclosporine). The indications for adalimumab treatment
were corticosteroid dependence in 41 patients (46.6%), cor-
ticosteroid resistance in 23 patients (26.1%), extraintestinal
manifestations in 14 patients (15.9%), and a combination of
corticosteroid dependence and extraintestinal manifestations
in ten patients (11.4%). The median duration of adalimumab
therapy was 13months (IQR, 621months), with a median
follow-up duration of 15.5 months (IQR, 1224 months).
The co-primary endpoints were defined as the proportion of
patients achieving clinical remission (partial Mayo score # 1)
at 4, 12, 24, and 54 weeks. The clinical remission rates were
17%, 28.4%, 36.4%, and 43.2% at 4, 12, 24, and 54 weeks,
respectively, with no significant differences between the
infliximab-nave and infliximab-exposed patients. Fifteen
patients (17%) achieved sustained clinical remission, defined
as a lasting clinical remission from week 12 up to 24 and
54 weeks. Among the 60 patients who were taking steroids
at baseline, 56.7% were able to discontinue steroids, and
a steroid-free remission was achieved in 24 of 60 patients
(40.0%) at week 54. Fifty-seven patients underwent baseline
and follow-up endoscopy after a median of 11months (IQR,
5.113.2months). An endoscopic remission was achieved in
28 (49.1%) of 57 patients, and 15 (26.3%) of the 57 achieved
complete mucosal healing. Overall, 25% (22 of 88) of the
patients required colectomy, with a median time to colectomy
of 5.5months (IQR, 313months). The rate of colectomy
was higher in the infliximab-exposed group than in the
infliximab-nave group (28.9% vs 10.5%), but this result
did not achieve statistical significance, probably because
of the small number of patients who ultimately required
surgery and the small number of infliximab-nave patients
enrolled in the study. In conclusion, in this large, real-life
cohort of refractory and difficult-to-treat ulcerative colitis
patients, adalimumab was shown to be effective at inducing
and maintaining a durable clinical remission and to have a
steroid-sparing effect.35
Safety
Adalimumab treatment is generally well tolerated. The
subcutaneous administration is associated with generally
mild injection site reactions that do not necessitate drug
discontinuation. The overall safety profile in the clinical
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trials in patients with ulcerative colitis was comparable to
that of placebo, and the rates of adverse events were similar
to the ones that emerged for the other approved indications
for adalimumab.36 No relevant warnings have emerged from
the real-life studies. However, in two studies, a worsening
of preexisting psoriasis, leading to drug withdrawal, was
recorded.24,28 Lastly, the fully human-designed features of
adalimumab reduce, but do not eliminate, the risk of antidrug
antibody development.22 The presence of human anti-human
antibodies (HAHA) and low trough serum adalimumab lev-
els have been reported to influence the long-term outcome
of adalimumab therapy in patients with Crohns disease.
Increased adalimumab discontinuation rates have also been
reported in Crohns disease patients with low trough serum
adalimumab concentrations. Furthermore, HAHA were
detected in 92% of Crohns disease patients with low trough
serum adalimumab levels during follow-up, probably reflect-
ing the increased clearance of the drug and the subsequent
loss of response. Finally, concomitant immunosuppressive
agents did not affect treatment outcomes, adalimumab trough
levels, or HAHA development.37
Conclusion
The treatment of ulcerative colitis depends largely on the
extension, severity, and behavior of the disease, and the tradi-
tional step-up approach with conventional drugs remains the
standard management approach. However, there are subsets
of patients who do not respond to conventional therapies or
in whom conventional therapies are contraindicated. In these
difficult-to-treat patients, the current guidelines recommend
the use of biological drugs. In the recent past, infliximab
was the only biological drug approved for the treatment of
patients with ulcerative colitis. Recently, after the publica-
tion of the results of the two pivotal, randomized ULTRA
12 trials, adalimumab was approved for use in patients
with moderately-to-severely active disease, nonresponders,
and those intolerant to conventional therapy. As often hap-
pens, the results of a clinical trial should be incorporated
into real-life clinical practice, where patients have already
experienced several therapies before, and may be intolerant
or not fully adherent to treatments. Therefore, the goal is to
select the candidates who will best benefit from the drug. The
emerging concept is that the ideal candidates for adalimumab
therapy are anti-TNF-nave outpatients with moderate-
to-severe corticosteroid- or immunosuppressive-refractory
ulcerative colitis. Short-term clinical responses, evaluated
after 812 weeks, seem to influence the long-term outcomes
and are associated with more durable clinical responses and
Drug Design, Development and Therapy 2013:7
Adalimumab in the management of ulcerative colitis
colectomy-free survival. Adalimumab also demonstrated a
steroid-sparing effect and a mucosal healing capacity, and
it may be a valid option for steroid-dependent patients. As
has now been demonstrated in pivotal trials and in several
real-life experiences, adalimumab is effective and safe for
treating patients with different types of ulcerative colitis,
including difficult-to-treat individuals.
Disclosure
AA received consultancy from AbbVie and MSD; lecture
fees from AbbVie, MSD, Chiesi, Ferring, Nycomed, and
Otsuka; and educational grants from AbbVie and MSD. LG
received educational grants from AbbVie, MSD. The authors
report no other conflicts of interest.
References
1. Dignass A, Eliakim R, Magro F, etal. Second European evidence-based
consensus on the diagnosis and management of ulcerative colitis part 1:
definitions and diagnosis. J Crohns Colitis. 2012;6(10):965990.
2. Silverberg MS, Satsangi J, Ahmad T, etal. Toward an integrated clinical,
molecular and serological classification of inflammatory bowel disease:
Report of a Working Party of the 2005 Montreal World Congress of
Gastroenterology. Can J Gastroenterol. 2005;19 Suppl A:536.
3. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and
colorectal cancer. A population-based study. N Engl J Med. 1990;
323(18):12281233.
4. Solberg IC, Lygren I, Jahnsen J, et al; IBSEN Study Group. Clinical
course during the first 10 years of ulcerative colitis: results from
a population-based inception cohort (IBSEN Study). Scand J
Gastroenterol. 2009;44(4):431440.
5. DHaens G, Sandborn WJ, Feagan BG, etal. A review of activity indices
and efficacy end points for clinical trials of medical therapy in adults
with ulcerative colitis. Gastroenterology. 2007;132(2):763786.
6. Ford AC, Achkar JP, Khan KJ, et al. Efficacy of 5-aminosalicylates
in ulcerative colitis: systematic review and meta-analysis. Am J
Gastroenterol. 2011;106(4):601616.
7. Dignass A, Lindsay JO, Sturm A, etal. Second European evidence-based
consensus on the diagnosis and management of ulcerative colitis part 2:
current management. J Crohns Colitis. 2012;6(10):9911030.
8. Rutgeerts P, Sandborn WJ, Feagan BG, etal. Infliximab for induction
and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;
353(23):24622476.
9. Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi Porro G.
Randomised controlled trial of azathioprine and 5-aminosalicylic
acid for treatment of steroid dependent ulcerative colitis. Gut. 2006;
55(1):4753.
10. Panaccione R, Rutgeerts P, Sandborn WJ, Feagan B, Schreiber S,
Ghosh S. Review article: treatment algorithms to maximize remission
and minimize corticosteroid dependence in patients with inflammatory
bowel disease. Aliment Pharmacol Ther. 2008;28(6):674688.
11. Armuzzi A, Pugliese D, Danese S, etal. Infliximab in steroid-dependent
ulcerative colitis: effectiveness and predictors of clinical and endoscopic
remission. Inflamm Bowel Dis. Epub February 27, 2013.
12. Laharie D, Bourreille A, Branche J, etal; Groupe dEtudes Thrapeu-
tiques des Affections Inflammatoires Digestives. Ciclosporin versus
infliximab in patients with severe ulcerative colitis refractory to intra-
venous steroids: a parallel, open-label randomised controlled trial.
Lancet. 2012;380(9857):19091915.
13. Moskovitz DN, Van Assche G, Maenhout B, etal. Incidence of colectomy
during long-term follow-up after cyclosporine-induced remission of severe
ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4(6):760765.
submit your manuscript | www.dovepress.com
295
Dovepress
Armuzzi etal
14. HUMIRA (adalimumab) subcutaneous injection [product monograph].
North Chicago, IL: Abbott Laboratories, Ltd; 2012.
15. Hanauer SB, Sandborn WJ, Rutgeerts P, etal. Human anti-tumor necro-
sis factor monoclonal antibody (adalimumab) in Crohns disease: the
CLASSIC-I trial. Gastroenterology. 2006;130(2):323333.
16. Colombel JF, Sandborn WJ, Rutgeerts P, etal. Adalimumab for main-
tenance of clinical response and remission in patients with Crohns
disease: the CHARM trial. Gastroenterology. 2007;132(1):5265.
17. Sandborn WJ, Rutgeerts P, Enns R, etal. Adalimumab induction therapy
for Crohn disease previously treated with infliximab: a randomized trial.
Ann Intern Med. 2007;146(12):829838.
18. Panaccione R, Colombel JF, Sandborn WJ, etal. Adalimumab sustains
clinical remission and overall clinical benefit after 2 years of therapy for
Crohns disease. Aliment Pharmacol Ther. 2010;31(12):12961309.
19. Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for
the treatment of fistulas in patients with Crohns disease. Gut. 2009;
58(7):940948.
20. Reinisch W, Sandborn WJ, Hommes DW, etal. Adalimumab for induc-
tion of clinical remission in moderately to severely active ulcerative colitis:
results of a randomised controlled trial. Gut. 2011;60(6):780787.
21. Sandborn WJ, van Assche G, Reinisch W, etal. Adalimumab induces
and maintains clinical remission in patients with moderate-to-severe
ulcerative colitis. Gastroenterology. 2012;142(2):257265.
22. Reinisch W, Sandborn WJ, Kumar A, Pollack PF, Lazar A, Thakkar RB.
52-week clinical efficacy with adalimumab in patients with moderately
to severely active ulcerative colitis who failed corticosteroids and/or
immunosuppresants. Gut. 2011;60 Suppl 1:A139A140.
23. Sandborn WJ, Colombel JF, DHaens G, etal. One-year maintenance
outcomes among patients with moderately-to-severely active ulcerative
colitis who responded to induction therapy with adalimumab: subgroup
analyses from ULTRA 2. Aliment Pharmacol Ther. 2013;37(2):
204213.
24. Feagan BG, Sandborn WJ, Thakkar RB, etal. Adalimumab induction
dose reduces the risk of hospitalizations and colectomies in patients
with ulcerative colitis during the first 8 weeks of therapy. Gut. 2012;
61 Suppl 3:A283.
25. Feagan BG, Sandborn WJ, Skup M, etal. Adalimumab therapy reduces
hospitalization and colectomy rates in patients with ulcerative colitis
among initial responders. Gut. 2012;61 Suppl 3:A164.
26. Colombel JF, Sandborn WJ, Wolf D, et al. Long term efficacy of
adalimumab for treatment of moderate to severe ulcerative colitis. Gut.
2012;61 Suppl 3:A80.
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27. Oussalah A, Laclotte C, Chevaux JB, et al. Long-term outcome of
adalimumab therapy for ulcerative colitis with intolerance or lost
response to infliximab: a single-centre experience. Aliment Pharmacol
Ther. 2008;28(8):966972.
28. Afif W, Leighton JA, Hanauer SB, et al. Open-label study of adali-
mumab in patients with ulcerative colitis including those with prior
loss of response or intolerance to infliximab. Inflamm Bowel Dis.
2009;15(9):13021307.
29. Hudis N, Rajca B, Polyak S, Zeilman CJ, Valentine JF. The outcome
of active ulcerative colitis treated with adalimumab. Gastroenterology.
2009;136(5 Suppl 1):A661.
30. Gies N, Kroeker KI, Wong K, Fedorak RN. Treatment of ulcerative
colitis with adalimumab or infliximab: long-term follow-up of a single-
centre cohort. Aliment Pharmacol Ther. 2010;32(4):522528.
31. Taxonera C, Estells J, Fernndez-Blanco I, et al. Adalimumab
induction and maintenance therapy for patients with ulcerative
colitis previously treated with infliximab. Aliment Pharmacol Ther.
2011;33(3):340348.
32. McDermott E, Murphy S, Keegan D, ODonoghue D, Mulcahy H,
Doherty G. Efficacy of adalimumab as a long term maintenance therapy
in ulcerative colitis. J Crohns Colitis. 2013;7(2):150153.
33. Ferrante M, Karmiris K, Compernolle G, etal. Efficacy of adalimumab
in patients with ulcerative colitis: restoration of serum levels after
dose escalation results in a better long-term outcome. Gut. 2011;
60 Suppl 3:A72.
34. Garca-Bosch O, Gisbert JP, Caas-Ventura A, et al. Observational
study on the efficacy of adalimumab for the treatment of ulcerative coli-
tis and predictors of outcome. J Crohns Colitis. 2012. Epub November 8,
2012.
35. Armuzzi A, Biancone L, Daperno M, et al. Adalimumab in active
ulcerative colitis: a real-life observational study. Dig Liver Dis. In
press 2013.
36. Burmester GR, Mease P, Dijkmans BA, et al. Adalimumab safety
and mortality rates from global clinical trials of six immune-mediated
inflammatory diseases. Ann Rheum Dis. 2009;68(12):18631869.
37. Karmiris K, Paintaud G, Noman M, etal. Influence of trough serum lev-
els and immunogenicity on long-term outcome of adalimumab therapy
in Crohns disease. Gastroenterology. 2009;137(5):16281640.
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